Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients

被引:11
作者
Doll, Julia [1 ]
Kolb, Susanne [1 ]
Schnapp, Linda [1 ]
Rad, Aboulfazl [2 ]
Ruschendorf, Franz [4 ]
Khan, Imran [5 ]
Adli, Abolfazl [2 ]
Hasanzadeh, Atefeh [2 ]
Liedtke, Daniel [1 ]
Knaup, Sabine [1 ]
Hofrichter, Michaela A. H. [1 ]
Mueller, Tobias [6 ]
Dittrich, Marcus [1 ,6 ]
Kong, Il-Keun [7 ]
Kim, Hyung-Goo [8 ]
Haaf, Thomas [1 ]
Vona, Barbara [1 ,3 ]
机构
[1] Julius Maximilians Univ, Inst Human Genet, D-97074 Wurzburg, Germany
[2] Sabzevar Univ Med Sci, Cellular & Mol Res Ctr, Sabzevar 009851, Iran
[3] Eberhard Karls Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen Hearing Res Ctr, D-72076 Tubingen, Germany
[4] Max Delbruck Ctr Mol Med Helmholtz Assoc, D-13125 Berlin, Germany
[5] Bacha Khan Univ, Dept Chem, Khyber Pakhtunkhawa 24420, Pakistan
[6] Julius Maximilians Univ, Inst Bioinformat, D-97074 Wurzburg, Germany
[7] Gyeongsang Natl Univ, Inst Agr & Life Sci, Div Appl Life Sci BK21plus, Dept Anim Sci, Jinju 52828, South Korea
[8] Hamad Bin Khalifa Univ, Neurol Disorders Res Ctr, Qatar Biomed Res Inst, Doha 34110, Qatar
关键词
CDC14A; DFNB32; autosomal recessive hearing loss; exome sequencing; splicing; frameshift; non-sense mediated mRNA decay; PHOSPHATASE; IDENTIFICATION; MUTATIONS; FRAMEWORK; DISEASE; DECAY;
D O I
10.3390/ijms21010311
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss.
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页数:14
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共 39 条
  • [11] Fromer Menachem, 2014, Curr Protoc Hum Genet, V81, DOI 10.1002/0471142905.hg0723s81
  • [12] Forty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics?
    Hilgert, Nele
    Smith, Richard J. H.
    Van Camp, Guy
    [J]. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH, 2009, 681 (2-3) : 189 - 196
  • [13] CDC14A phosphatase is essential for hearing and male fertility in mouse and human
    Imtiaz, Ayesha
    Belyantseva, Inna A.
    Beirl, Alisha J.
    Fenollar-Ferrer, Cristina
    Bashir, Rasheeda
    Bukhari, Ihtisham
    Bouzid, Amal
    Shaukat, Uzma
    Azaiez, Hela
    Booth, Kevin T.
    Kahrizi, Kimia
    Najmabadi, Hossein
    Maqsood, Azra
    Wilson, Elizabeth A.
    Fitzgerald, Tracy S.
    Tlili, Abdelaziz
    Olszewski, Rafal
    Lund, Merete
    Chaudhry, Taimur
    Rehman, Atteeq U.
    Starost, Matthew F.
    Waryah, Ali M.
    Hoa, Michael
    Dong, Lijin
    Morell, Robert J.
    Smith, Richard J. H.
    Riazuddin, Sheikh
    Masmoudi, Saber
    Kindt, Katie S.
    Naz, Sadaf
    Friedman, Thomas B.
    [J]. HUMAN MOLECULAR GENETICS, 2018, 27 (05) : 780 - 798
  • [14] Coupled 5′ Nucleotide Recognition and Processivity in Xrn1-Mediated mRNA Decay
    Jinek, Martin
    Coyle, Scott M.
    Doudna, Jennifer A.
    [J]. MOLECULAR CELL, 2011, 41 (05) : 600 - 608
  • [15] Cryptic splice sites and split genes
    Kapustin, Yuri
    Chan, Elcie
    Sarkar, Rupa
    Wong, Frederick
    Vorechovsky, Igor
    Winston, Robert M.
    Tatusova, Tatiana
    Dibb, Nick J.
    [J]. NUCLEIC ACIDS RESEARCH, 2011, 39 (14) : 5837 - 5844
  • [16] Quality and quantity control of gene expression by nonsense-mediated mRNA decay
    Kurosaki, Tatsuaki
    Popp, Maximilian W.
    Maquat, Lynne E.
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2019, 20 (07) : 406 - 420
  • [17] Fast and accurate long-read alignment with Burrows-Wheeler transform
    Li, Heng
    Durbin, Richard
    [J]. BIOINFORMATICS, 2010, 26 (05) : 589 - 595
  • [18] Are splicing mutations the most frequent cause of hereditary disease?
    López-Bigas, N
    Audit, B
    Ouzounis, C
    Parra, G
    Guigó, R
    [J]. FEBS LETTERS, 2005, 579 (09) : 1900 - 1903
  • [19] Nonsense-mediated mRNA decay: Splicing, translation and mRNP dynamics
    Maquat, LE
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2004, 5 (02) : 89 - 99
  • [20] Mazzoli M., 2003, Audiological Medicine, V1, P148, DOI [10.1080/16513860301713, DOI 10.1080/16513860301713]